Connective tissue activation. xxxvi. the origin,variety, distribution,and biologic fate of connective tissue activating peptide–iii isoforms: characteristics in patients with rheumatic,renal, and arterial disease

Objective. To determine the origin, distribution, and biologic fate of platelet-derived connective tissue activating peptide–III (CTAP-III), to define the relative amounts of the antigen forms (CTAP-III, betathromboglobulin [β-TG], neutrophil activating peptide–2 [NAP-2]) in plasma of normal persons and those with rheumatic or end-stage renal disease, and to define the isoforms of CTAP-III in platelets, plasma, transudates, and tissue deposits. Methods. CTAP-III in plasma was measured by enzyme-linked immunosorbent assay, and growth promoting activity of CTAP-III isoforms was tested in synovial and peritoneal cell cultures by measuring increased synthesis of ¹⁴C-glycosaminoglycan (¹⁴C-GAG) and ³H-DNA. Isolated CTAP-III was characterized by Western blotting, microsequencing, and mass spectrometry. Results. CTAP-III was the primary isoform of this antigen family in normal platelets and platelet-rich plasma; β-TG and NAP-2 accounted for <1% of CTAP-III isoforms. Previously undescribed isoforms, i.e., CTAP-III des 1, des 1–2, des 1–3, and a phosphate adduct of CTAP-III, were observed in varying amounts. Elevated plasma levels of CTAP-III antigen were found in a substantial fraction of rheumatic disease patients: 24% of those with rheumatoid arthritis, 36% of those with systemic sclerosis, and 15% of those with systemic lupus erythematosus. All 10 patients with end-stage kidney disease had marked elevations of plasma CTAP-III levels, which stimulated DNA and GAG synthesis by peritoneal cells in culture. Only large isoforms (such as CTAP-III) were detected in venous plasma of normal subjects, rheumatic disease patients, and patients receiving long-term dialysis. Normal human spleen and kidney contained substantial (μ/gm) amounts of CTAP-III and traces of an isoform with the electrophoretic mobility of CTAP-III des 1–15/NAP-2. Liver, lung, and urine contained lesser (ng/gm) amounts of CTAP-III. Conclusion. These data show that, among the 10 known isoforms, intact CTAP-III itself was the major circulating isoform (>90%), and β-TG was the most rare (0–1%). Deposition of CTAP-III in tissues, such as synovium, spleen, and kidney, is associated with partial processing to NAP-2–like isoforms and the potential to induce neutrophil and fibroblast activation in patients with rheumatic or end-stage renal disease.     

Pilot study of antithymocyte globulin in systemic sclerosis

Objective. Between June 1, 1992 and August 31, 1994 we conducted an open pilot study of antithymocyte globulin (ATGAM; Upjohn, Kalamazoo, MI) in 10 patients with early systemic sclerosis (SSc) to assess whether this agent might prevent the progression of cutaneous and pulmonary involvement in this disease. Methods. Adult patients with early SSc (<3 years) and evidence of progressive skin and pulmonary disease were enrolled. All patients were hospitalized and received a single course of intravenous ATGAM, at a dosage of 10 mg/kg over 4 hours, on 5 consecutive days. Patients were followed up at weeks 1, 2, 3, and 4, and months 2, 4, 6, and 12. Patients were considered to be improved if the Rodnan skin score decreased ≥25%, to be worse if the skin score increased ≥25%, and to be not improved if the skin score was within 25% of baseline. For pulmonary involvement, patients were considered to be improved if either the diffusing capacity for carbon monoxide or the forced vital capacity was increased ≥10%, worse if decreased by ≥10%, and stable if within 10% of baseline. Results. Most patients tolerated the treatment well, although 1 patient developed an allergic reaction necessitating discontinuation of treatment, 1 developed a serum sickness reaction after completion of therapy, and 1 developed a central venous access–related axillary vein thrombosis. Two patients died of SSc-related complications during the followup period. At 12 months, only 2 patients showed improvement in both skin and pulmonary function measures, whereas 5 patients were worse and 3 were stable. Conclusion. At the dosage administered in this study, ATGAM appears ineffective in improving the skin and pulmonary features of SSc.     

Idiopathic inflammatory myopathy of the antisynthetase (jo-1) type associated with noncaseating granulomas

The idiopathic inflammatory myopathies are a heterogeneous group of syndromes that share the finding of chronic muscle inflammation. Recently, serologic subtyping of autoantibodies found in patients with these syndromes has been used to identify distinct clinical entities. We describe a 36-year-old woman who, based on the findings of polymyositis documented by both electromyography and muscle biopsy, features of Raynaud's phenomenon, symmetric polyarthritis, “mechanic's hands,” and Jo-1 antibody positivity, was considered to have the antisynthetase subset of idiopathic inflammatory myopathy. In addition, the patient had granulomatous synovitis, and noncaseating granulomas were found in a breast nodule. This is the first published report of granuloma formation in the antisynthetase syndrome.     

Effect of nintedanib in patients with progressive pulmonary fibrosis associated with rheumatoid arthritis: data from the INBUILD trial

Clinical Rheumatology - Some patients with rheumatoid arthritis develop interstitial lung disease (RA-ILD) that develops into progressive pulmonary fibrosis. We assessed the efficacy and safety of...